of Head and Neck Cancer and Relation to Inflammation

Treatment of Head and Neck Cancer and Relation to Inflammation

Rohaizam Japar Jaafar1, *, Zulkifli Yusof1, Zakinah Yahaya2


Over the past decades, the survival rate of head and neck cancers has not significantly changed. Recently, the importance of the inflammatory responses in head and neck cancer has been a hot topic and of increasing interest. There has been suspicion about the relationship between inflammation and carcinogenesis, and thus, many works had proven these relations. Manipulation of the inflammatory mediators has been experimented with, to reduce the tumor burden, treat as well as prevent the cancer occurrence or second primary. This chapter summarizes the relationship between inflammation and cancer, emphasizing epidemiological and clinical evidence and proposing the current potential targets of anti-inflammatory agents for the therapeutic approach of head and neck cancer (HNC). We hope this knowledge will help us combat carcinogenesis and reduce the morbidity of the current conventional treatment for a better quality of life.

Keywords: Head and neck cancer, Inflammation, Treatment.

* Corresponding author Rohaizam Japar Jaafar: Hospital Sultanah Bahiyah, Alor Setar, Kedah, Malaysia;
Tel: +60126306022; E-mail:


The investigation toward inflammatory-associated carcinogenesis and approaches to reach the inflammatory targets is a relatively new area in cancer research [1]. When Rudolf Virchow introduced the term inflammation-related carcinogenesis in 1863, many epidemiological studies and research support the theory only years later [1, 2]. To date, inflammation is widely recognized as a hallmark for carcinogenesis. The idea for inflammation-related malignancies allows us to target the inflammatory response as therapeutic management of cancer at the molecular level.

The role of medical treatment in head and neck cancer has evolved over the years with a better understanding of tumor genetics and biology. Although it is a clear

connection that an inflammation leading to cancer; for example, hepatitis due to hepatitis B virus or C or toxic compounds as the initiation in the development of hepatocellular carcinoma, association between chronic esophagitis and Barrett’s metaplasia with esophageal cancer, chronic pancreatitis and pancreatic cancer, inflammatory breast cancer as a result of unresolved breast inflammation and Helicobacter pylori infection with gastric adenocarcinoma [2], but the inflammation-related head and neck cancer is still new. Understanding inflammatory pathway blockage, overexpression of inflammatory mediators and targeting the cancer microenvironment can be the promising approach for head and neck cancer treatment.

In 2008, about 16.1% of newly diagnosed cancers were related to infections [3], while epidemiologic studies indicate that at least 20% of all cancers begin as a direct consequence of chronic inflammatory processes [2]. Undoubtedly, inflammation-related oncogenesis is complex; it involves numerous cells and mediators through multiple mechanisms. There is a crosstalk between two pathways, the extrinsic pathway, driven by non-cancerous cells and the environment, and the intrinsic pathway, which is driven by oncogenes expression. The extrinsic insult such as infection, obesity, smoking, alcohol, microparticles, for example, silica and asbestos, and chronic inflammatory diseases is an established risk factor related to chronic inflammation [2, 3]. For example, cigarette smoking is proven to modulate an immune response. The effects are complex; both pro-inflammatory and suppressive effects may be initiated. Nevertheless, it contains toxins and bacterial lipopolysaccharide responsible for mucosal damage, and molecular derangements leading to oncogenesis by increasing cytogenic abnormalities, inactivation of tumor suppressor genes, and changes in the intracellular signaling pathway. As a direct consequence, smoking impairs immunity in the oral cavity, promotes gingival and periodontal disease and oral cancer. Smoking is also a risk factor in developing premalignant lesions, including leukoplakia and erythroplakia, which can progress to invasive carcinomas [4].

On the other hand, the intrinsic factor can be triggered by mutations, recruitment, and activation of inflammatory cells [4, 5]. It directly affects the initiation, angiogenesis, cell migration, progression, and aggressiveness of the tumor. At a molecular level, this process activates the apoptotic pathway either by down-regulate pro-apoptotic or up-regulate anti-apoptotic molecules. Inflammatory cytokines are major inducers that play a vital role in oncogenesis, and even there is emerging evidence that tumor cells and tumor-associated leucocytes can produce inflammatory cytokines and chemokines by themselves [5]. The inflammatory cytokines are tumor necrosis factor-α (TNF-α), interleukin- 1β (IL-1β) and interleukin-6 (IL-6), and chemokines are prostaglandins, oncogenes, cyclooxygenase-2, inducible nitric oxide synthase, 5-lipoxygenase, matrix metalloproteinases, vascular endothelial growth factor, hypoxia-inducible factor-1α, nuclear factor-κβ (NF-κβ), nuclear factor of activated T-cells, signal transducers and activators of transcription 3-STAT3, activator protein-1 (AP-1), cAMP, and enhancer-binding protein. Additionally, activation of various kinases, including Iκβ kinase (IKK), protein kinase-C, mitogen-activated protein kinase, and phosphoinositide-3 kinase/protein kinase B (PI3K)/AKT, participates in inflammation-related oncogenesis [610]. Anti-inflammatory agents are believed to alter the tumor microenvironment, reduce cell migration, increase apoptosis, and increasing sensitivity to other therapy [3, 6].

There are several genetic alterations associated with chronic inflammation in head and neck cancer (HNC). An example of the interplay between inflammation and genetic alteration is HPV-related oropharyngeal squamous cell carcinoma. They present at a younger age, who is non-smoker and do not consume alcohol. HPV-16 DNA has been found in up to 72%, and inactivation of p16 is a frequent event witnessed in >80% of oropharyngeal tumour specimens [1113]. The HPV integrates into host DNA expresses oncoproteins E6 to target the tumor suppressor genes p53 and E7, which act on the pRb for ubiquitin-mediated intracellular degradation, inactivate the normal cell cycle resulting in oncogenic transformation [11]. HPV-16 and HPV-18 are the most common oncogenic variant [14, 15]. Notably, it has been found that 50% of all oropharyngeal tumor specimens contain p53 mutations [16].

Another example is the Epstein-Barr virus. It is known to have a causal relationship in lymphoma, nasopharyngeal carcinoma, and gastric carcinoma, in which it mainly infects human lymphocytes and oropharyngeal epithelial cells. Multiple and diverse pathways are involved in EBV-related oncogenesis. The interaction of virus and host genes during its latency period leads to G1/S phase transition and inhibition of cell apoptosis. The latent proteins and miRNAs encoded by EBV activates the oncogenes such as Bcl-2 and MYC, activate signaling pathways such as NF-κB, JAK/STAT, and PI3K/Akt, and inhibit tumor suppressor genes such as p53, PTEN, and p16INK4A. EBV is known to facilitate the oncogenic courses with specific oncogene activation [17].

In this chapter, we would like to list several strategies, possibly to reduce the tumor burden, treat and prevent cancer. There is an increasing number of FDA-approved anti-inflammatory agents concerning cancer. Since monotherapy or conventional modality insufficiently to eradicate cancer, a combination supposedly to be introduced [6]. The majority of agents target rapidly proliferating cells, resulting in cell death. Others can alter the tumour or the therapeutic agents’ pharmacokinetics and pharmacodynamics on the molecular level to increase apoptosis’s efficacy. For example, steroid administration can change the pharmacokinetics of chemotherapeutic drugs to decrease their toxicity and increase their activity in the tumour leading to differences in the concentration, half-life, and clearance of the active metabolite. The anti-inflammatory agents may also have synergistic effects to sensitize cancer cells to conventional cancer treatment. While these compounds may eventually prove their utility, more emphasis should be placed on the agents for clinical use to bring about the best benefit for the patients [6].


Non-selective Agent to Arrest Inflammation

Aspirin and NSAIDs

In 1897, Hoffmann discovered acetylsalicylic acid in a pure and stable form and was registered under the name “Aspirin” two years later. It came from ‘a’cetyl, and ‘spir’ came from the plant in which salicylic acid had initially been isolated, spirea ulmania. Only a decades later, in 1971, Sir John Vane discovered aspirin as a prostaglandin synthetase inhibitor. Eventually, there is emerging evidence showing the benefits of aspirin in cancer and led to the discovery of NSAIDs as chemoprevention agents [1820]. Although the use of NSAIDs such as aspirin, ibuprofen, indomethacin, and celecoxib in the long term has been associated with the reduced risk of developing colorectal, esophageal, lung, gastric, breast, prostate and ovarian cancer and cancer-related mortality by 20% to 25%, its role in preventing head and neck cancer remains investigational [2, 6, 2023]. Experimental studies show that NSAIDs can arrest tumor growth in HNSCC, showing the potential to reduce the risk of second primary and as a chemopreventive agent [4].

NSAIDs non-selectively inhibit COX of the arachidonic acid metabolism pathway and inflammatory mediators such as prostaglandins and leukotrienes [24]. Prostaglandin E2 is produced by PGE synthase causes increased cell proliferation, inhibition of apoptosis, and stimulation of angiogenesis. It is synthesized in multiple-steps. Arachidonic acid is first released from membrane-bound phospholipids by phospholipase A2, then converted to prostaglandin H2 mediated by COX and finally PGE2. This step recognition is essential to target the synthesis of PGE2 [20]. A two-step model has been implicated by Haddad et al. suggesting the inactivation of PGE2 located in the developing tumor microenvironment is first mediated by the PGT, which engages carrier-mediated membrane transport of prostaglandins (PGE2, PGF2a, and PGD2) from the extracellular to the cytoplasm and the second step involves catabolization of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in the cytoplasm and inactivates PGE2 [25].

The binding of prostaglandin to their receptors results in the activation of adenylyl cyclase resulting cyclic AMP (cAMP). PGE2 and elevated COX-2 contributes to carcinogenesis and cancer progression [2629]. There are two isoforms of COX, which one of those have differences in the therapeutic and side effects. Prostaglandins produced by COX-1 play a role in platelet function, renal tubules, and gastrointestinal epithelium, whereas COX- 2 is involved in pain and inflammation [30]. It has been shown that COX-2 has an essential role in the biology of HNSCC [31]. COX-2 is the most common anti-cancer inflammatory target, although numerous other targets such as NF- κB, cytokines/cytokines receptors, chemokines/receptors, FGF/R, and VEGF have also been examined. Several studies have suggested that the anti-tumor activity of COX-2 inhibitors is at least partly unrelated to their inhibition of cyclooxygenase [6]. The correlation between COX-2 expression and head and neck tumor indicates size and prognosis [31].

The mechanism by which NSAIDs inhibit tumor development is thought through the inhibition of COX-2 and, consequently the synthesis of PGs [31]. The elevated COX-2 has been postulated through induced EGFR- mediated activation of the cell survival cascade (AKT/c- FLIP/COX-2) and regulates the tumor microenvironment through IL-17 results in anti-apoptotic activity and promote macrophage differentiation, respectively [32, 33]. Inhibition of several transduction pathways, including Wnt–β catenin, PIK3CA/ AKT/PTEN, and NF-κB, has been postulated because patients with PIK3 mutations and those with mutations within the NF-κB pathway could have reduced cancer risk after use of NSAIDs [3436]. On the other hand, high-dose aspirin is also thought to induce apoptosis through COX-independent mechanisms such as activation of caspases, p38 MAP kinase, and ceramide pathway, releasing mitochondrial cytochrome C and regulating several different targets, for example, ALOX15, PAWR (pro-apoptotic gene), and BCL2L1 (anti-apoptotic gene) [37].

As high as 40% improvement and reduced recurrence seen with colorectal carcinoma using COX-2 inhibitors (rofecoxib and celecoxib) and current phase 3 clinical study recommended it as adjuvant therapy, but there is a mixed result of NSAIDs usage in preventing head and neck cancer [34, 38]. In 2006, Jayaprakash et al. and Caponigro et al. reported a risk reduction across all the primary tumors with higher risk reduction for oral cavity and oropharyngeal cancers. Moderate smokers or moderate drinkers have the most significant risk reduction, and the protective effect was higher in women [39]. As opposed to that, Bonomi et al. showed a significant reduction in HNSCC risk with aspirin use for laryngeal cancers [4]. Although in-vitro studies suggest an anti-tumor effect of COX inhibitors in head and neck cancer, Gillespie in 2007 found no difference in head and neck cancer recurrence or overall survival in COX inhibitor users compared to non-users [40]. A few years later, Ahmadi et al. stated that NSAIDs use was associated with a 75% reduction in risk of developing HNSCC, while Becker et al., with large scale epidemiology study came out indicating that aspirin and NSAID use do not affect overall HNSCC risk. However, he suggests that regular ibuprofen use may be beneficial in HNSCC prevention [21, 23]. Kim et al. concluded that celecoxib’s cytotoxicity effects are unpredictable and may vary in a clinical setting. This warrants further investigations as a combined alternative [41].

Bin Yang et al. showed that COX-2 expression could be a prognostic factor correlated with a high risk of lymph node metastasis. An advanced TNM stage in HNSCC indicates poor overall survival, recurrence-free survival and disease- free survival in patients with HNSCC [42] but a year later, Kim et al. indicating that aspirin and NSAIDs do not affect survival, recurrence, or second cancer occurrence in patients with HNSCC. The cumulative aspirin dose before HNSCC diagnosis did not affect survival outcomes [43]. Recently, Hedberg et al. concluded that regular NSAIDs usage, irrespective of HPV status, likely confers a statistically and clinically significant advantage in DSS as well as OS in patients with PIK3CA-altered HNSCC, through the PI3K and COX pathways [44].

A few authors have proposed a combination of treatment. COX-2 inhibitors have demonstrated synergy when combined with EGFR inhibitors in preclinical models [45, 46]. Based on a recent in-vivo study using combined EGFR and COX-2 in very high-risk dysplastic oral leukoplakia patients, a preliminary data of a Phase I study of daily celecoxib, combined with weekly docetaxel, cisplatin and concurrent radiotherapy in patients with locally advanced HNSCC have shown significant combined regimes to target both pathways [47]. Crosstalk between COX-2 and EGFR signaling pathways in HNSCC suggests that a combined approach is justified and more effective inhibiting growth and angiogenesis rather than monotherapy [41, 48, 49].

Celecoxib, with erlotinib and reirradiation, was shown to be a feasible and clinically active regimen in a population of patients with recurrent HNSCC who had a poor prognosis [48]. A combination of apricoxib with erlotinib in non- small-cell lung cancer showed a 60% disease control rate [50]. Apricoxib, compared to celecoxib in HNSCC setting, showed better up-regulation of E- cadherin expression and down-regulation of vimentin, which was implicated as a sensitivity marker to EGFR TKI [51]. Targeted therapy combination Huang et al. investigated a combined treatment of nimotuzumab and celecoxib in poorly differentiated NPC with promising results [52].

Not surprisingly, in oral premalignant lesions (OPL), the COX-2 is overexpressed too. However, clinical trials using non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit COX-2 have not been very successful in the chemoprevention of OPL. Ketorolac, as an oral rinse, a non-selective COX inhibitor, failed to show any significant reduction in oral leukoplakia. As a specific inhibitor of COX-2, Celecoxib failed to control oral premalignant lesions too [53]. Celecoxib was ineffective in controlling oral premalignant lesions in a recent randomized controlled trial [54].

Nevertheless, due to their non-selective isozymes, long-term NSAID can result in unwanted and paradoxical effects, including renal failure and gastrointestinal bleeding, peptic ulcers, and intestinal inflammation that may increase cancer risk. Furthermore, NSAIDs also can cause potentially life-threatening thromboembolic complications, for example, pulmonary embolism, myocardial infarction, and stroke. Few selective COX-2 inhibitors have been withdrawn from the market (rofecoxib in 2004 and valdecoxib in 2005) except celecoxib that is still available in the United States and Europe [20, 5560].


Although there are no formal studies investigating steroid as monotherapy in head and neck cancer, but rather as a co-administration to reduces edema and pain. Steroids are believed to interact with DNA-regulators genes, which results in apoptosis via TP53-independent signal transduction pathways. It modulates, enhances, or activates up or down-regulation of proliferation, enhances cellular glutathione and ABCB1 expression, induces of metallothionein synthesis, and stimulate O6-methylguanine-DNA methyl-transferase activity which responsible for DNA repair [60].

The intermediate and long-acting corticosteroids have been investigated for its potential therapeutic and chemoprotective effects. Dexamethasone, hydrocortisone, and prednisolone have been tested for its anti-inflammatory function by inhibition of various cytokines production [61]. Several in-vivo studies demonstrated that dexamethasone treatment could decrease tumor growth in renal, breast, lung, and hematological malignancies [6163]. It is reported that dietary dexamethasone administration to exposed mice to tobacco smoke leads to a decrease in lung tumor incidence for more than 60% [2, 61].

Again, pretreatment with dexamethasone can enhance the effects of conventional therapies in animal studies. A co-administration of dexamethasone in an animal model with glioma, breast, lung, and colon cancers led to a 2-4- fold increment in the efficacy of carboplatin and/or gemcitabine [36, 64, 65]. In a recent clinical trial, patients with relapsed multiple myeloma, dexamethasone combined with carfilzomib, and lenalidomide showed significantly improved progression-free survival of the patients [62]. In clinical settings, high-dose dexamethasone (up to 16 mg twice a day) before chemotherapy improved the efficacy of chemotherapy drugs [36].


Statins are common and usually prescribed for dyslipidemia. Its role repeatedly demonstrated an onco-protective, radiosensitizing, and pro-differentiating effects in head and neck cancer in vitro. A phase I clinical trial has demonstrated stable disease in HNC with very high-dose lovastatin. In a retrospective large cohort study suggesting significant overall survival and disease-free survival in patients with the larynx, hypopharynx, and nasopharynx SCC concomitantly taking statins the time of cancer diagnosis [66].

Statins have usually been used as an adjunct treatment combined with 5- fluorouracil, cisplatin, and doxorubicin, although monotherapy as a chemopreventive approach has been reported [67, 68]. Statins have the pro-apoptotic effect by inhibiting HMG-CoA reductase, thus arrest the synthesis of isoprenoids that is essential for membrane localization and activation of signaling proteins such as ras, rho, and rac [69]. Besides, a downregulation of the RAF/MEK/ ERK pathway, inhibition of degradation of cell-cycle regulators p21 and p27, c-Myc activation, and proinflammatory pathways (NF-kB and COX2) further increased its apoptotic effects [70].

A real benefit of statin usage as head and neck anticancer still questionable and not as a standard treatment yet as it requires a high dose to achieve the effects. Some experimental studies showed a protective effect for colorectal, lung, liver, breast, and renal cell carcinoma while others do not [7182]. In 2014, Diakos et al. reported a 90% risk reduction of inflammatory bowel disease-related colorectal cancer if co-treatment with statin [83, 84]. Of note, some authors still believe the promising effects of statins as adjunct treatments at a safer dose.

Targeted Strategies in the Tumor Microenvironment Via Cytokines, Chemokines and Specific Enzymes Manipulation

Several cytokines and growth factors also activate signal pathways that promote the malignant phenotype. TNF-α, IL-1, HGF, and their receptors promote activation of the mitogen-activated protein kinase-activator protein-1 (MAPK- AP-1), nuclear factor-kappa B (NF-κB), and phosphati-dylinositol-3 kinase (PI3K)/Akt pathways [85]. The knowledge of immunomodulatory directed towards specific cytokines and chemokines has been an increased role in cancer therapy. As initial works are targeted for a non-cancer inflammatory disease with anti-TNF α and anti-interleukin-6 therapies, there has been a little experience in patients with cancer [86]. A recent discovery of the signaling pathways, especially transforming growth factor-β (TGF-β) and PTEN/PI3K/Akt/mTOR pathways, allows us to understand head and neck oncogenesis [87].

Cytokines include interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), and growth factors. Cytokine plays an essential role in the initiation, regulation, and maintenance of inflammatory and immune responses. They are divided into pro-inflammatory (e.g., IL-1, IL-6, IL-8, TNF-α, and IFN-γ) and anti-inflammatory e.g., IL-4, IL-10, TGF-β, and vascular endothelial growth factor (VEGF). It is understood that high levels of pro-inflammatory cytokines play a role in the development of HNSCC [88]. High levels of IL-1a, IL-6, IL- 8, granulocyte-macrophage colony-stimulating factor (GM-CSF), growth- regulated oncogene-(a) GRO1, VEGF, and hepatocyte growth factor (HGF) have been involved in the development of HNSCC [89].

Pro-inflammatory cytokines are produced by macrophages, B and T lymphocytes, endothelial cells, and fibroblasts involved in the promotion of cell proliferation, induction of angiogenesis, autophagy, and inhibition of apoptosis. TNF-α and interferon-γ induce autophagy, a cellular degradation process involving the amino acid recycling for cellular survival and proliferation [9092]. Anti-inflammatory cytokines such as IL-10 are produced by CD8+T cells inhibits NF-κB signaling through IκB kinases and unbinding NF-κB DNA [9395]. In clinical practice, it shows that low levels of cytokines and growth factors are associated with response to therapy and high levels are associated with poor outcomes in patients with HNSCC receiving chemotherapy and radiation [96].

CXCR4 is the most studied chemokine receptor. The antagonists, plerixafor is now in clinical use in non-Hodgkin lymphoma and multiple myeloma undergoing autologous stem cell transplantation. Trabectedin, a new cytotoxic drug, has shown selective cytotoxicity to tumor-associated macrophages and circulating monocytes via caspase-8-dependent apoptosis and inhibits inflammatory mediators such as CCL2, interleukin-6, and CXCL8 in soft-tissue sarcoma and ovarian cancer [97100].

IL-1β: IL-1β is one of an essential inflammatory regulator that promotes tumor progression through an accumulation of MDSCs which inhibit anti-cancer activity [101103]. This is showed with an experimental study using IL-1R– deficient mice with breast carcinoma that have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression [104]. Although the IL-1 antagonist has been used in the clinic to treat rheumatoid arthritis and autoinflammatory syndromes [101], its usage for anti-cancer still on trial. Anankira, a recombinant IL-1R antagonist, is used in phase 2 clinical trial for multiple myeloma, showed improved disease stability. Currently, Anakinra is being tested for advanced pancreatic, breast and colon cancer [102, 103].

IL-6: IL-6 promotes oral oncogenesis by enhanced secretion of matrix metalloproteinases 1 and 9 and activate STAT-1 and STAT-3 phosphorylation via IL-6 receptors and Janus family kinases (JAk). Moreover, IL-1β also stimulates Snail-1 and inhibits Cdh1 expression in HNSCC and further enhanced IL-8 and VEGF expression, which all of this causes neo-angiogenesis, tumor infiltration, and metastasis [105116]. Chen and Bigbee reported an elevation of IL-6 levels in serum and saliva of patients with head and neck cancers to have a significant relation with staging and response to therapy [117, 118]. Recently, IL-6 becomes a potential target for cancer prevention. Toclizumab, an FDA-approved anti-IL-6 receptor monoclonal antibody, is being tested in combination with albumin-bound paclitaxel plus gemcitabine for pancreatic cancer [3] while Siltuximab has been tested in ovarian, prostate and renal cancer, with some promising result [107, 108].

TNF-α: Although TNF-α is a critical pro-inflammatory cytokine, its role in carcinogenesis is controversial. TNF-α acts via two receptors TNFR1 and TNFR2. TNF-R1 (p60) is the initiator, expressed in all cell types and contains the death domain (DD) that is important in apoptosis whereas TNF-R2 (p80) is expressed mainly in immune cells and does not contain the death domain (DD) [119122]. It is postulated that the tumor-promoting mechanism is based on ROS and RNS, which can induce DNA damage and facilitate oncogenesis in a complex cascade [123125]. Infliximab, a recombinant IgG1 monoclonal antibody specific for TNF-α was initially developed for rheumatoid arthritis, but is now undergoing phase 2 studies in breast and renal cell cancer [100, 126]. Therapeutic use TNF-α cascade manipulation such as Etanercept, Adalimumab, Golimumab, and Certolizumab has shown limited clinical response in TNFα- regulated cytokines in ovarian, breast, pancreatic, and renal cancers [3, 127].

Controversy remains regarding the use of anti-TNF-α drugs given emerging toxicities and possible association with the development of new malignancies [100]. Significant side effects of this anti-TNF-α agents are an infection such as tuberculosis, varicella, and other opportunistic infections, and more importantly, a malignancy itself. The risk of non-Hodgkin’s lymphoma and skin cancer has been reported with TNF-α blocker. Therefore, its use needs to be carefully assessed because of the divergent outcomes [128130].

NF-κB, STAT-3, HIF-1: NF-κB and its pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8) are activated in HNSCC tumor specimens [1, 131]. NF-κB promotes leukocyte chemoattractant proteins ligand (CXCL-12, CCL-2, and CCL-3), COX-2, and endothelial adhesion molecules such as E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1, that leads to inflammatory reactions [132, 133]. Nevertheless, NF-κB has a dual effect on inflammation. One, the activation of NF-κB, activates cytotoxic response against cancer cells NF-κB, and second, the activation increases the expression of ROS or inducible NO synthase resulting in cell proliferation, anti-apoptosis and genetic instability which promotes oncogenesis [1, 134136]. Therefore, blocking NF-κB function in HNSCC will arrest tumor growth and reduce the expression of other chemokines-associated-pro- inflammatory molecules such as IL-6 and IL-8 [1, 131]. Inhibition of NF-κB is also known to sensitize cancer cells to TNF-α treatment [137139].

NF-κB signaling is interconnected with STAT3 and HIF-1 pathways, co- regulating with numerous oncogenic and inflammatory genes [140143]. STAT- 3 is stimulated and activated by IL-6, IL-11, IL-12 IL23, and various growth factors, mediates a protumorigenic response in the tumor microenvironment. Therefore, inhibition STAT-3 indirectly mediate tumor regression and provides a rational strategy to block carcinogenesis at an early stage [144146].

HIF-1α is mediated by the recruitment of the NF-κB complex to the HIF-1α promoter. HIF-1α promotes chemoresistance, angiogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism, and genomic instability [147, 148].

Immunotherapy in Head and Neck Cancer: An Immunotherapeutic Approach and Current Trials

In contrast to the inflammatory modulators, as we have discussed earlier, the critical strategy of an immunotherapeutic agent is to augment the immune response against tumor cells, facilitate the various immune cells and target directly towards the malignant cells. Current trials of immune therapeutic-based approaches predominantly comprise immune checkpoint inhibitors, adoptive cell transfer, and vaccines [149]. Most of these agents are still under trials [149, 150] and might not be included in our discussion.

Checkpoint Inhibitors

Checkpoint inhibitors are antibodies that bind to the checkpoint receptor on the T-cell and prevent it from binding to the inhibitory ligand on the tumor cell, which triggers the immune response. The immune checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD ligand are the most common targets in the clinical trials [149, 151]. A favorable outcome has been observed using these agents, and these are some of the examples used in head and neck cancers.

Ipilimumab blocks the CTLA-4 receptor, which prevents T-cell inhibition and enables an effective response against the tumor. A combined treatment of Ipilimumab and nivolumab for malignant melanoma [152] and non-small-cell lung carcinoma [153] showed a tolerable safety profile and encouraging response rate than Ipilimumab as a single agent [154]. A randomized, double-blind, phase II study of Nivolumab combined with Ipilimumab versus placebo in recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) is currently ongoing [155].

Pembrolizumab binds to the PD-1 receptor on the T cell and blocks the binding of the PD-1 ligand on the tumor cell, thus prevents immune suppression of the PD-1 ligand. Based on encouraging results in KEYNOTE- 012 [156, 157] and KEYNOTE-055 trials [158]. Pembrolizumab was the first FDA-approved drug for patients with progressive recurrent or metastatic SCC of the head and neck on or after treatment with platinum-containing chemotherapy. An undergoing phase III trial measures progression-free survival and overall survival of pembrolizumab in first-line treatment of recurrent/metastatic HNSCC compare pembrolizumab as monotherapy versus combination with chemotherapy [159]. The safety and efficacy of pembrolizumab given with chemoradiation (CRT) are yet to be determined in KEYNOTE-412 [160].

Nivolumab has a similar mechanism of action as pembrolizumab. It blocks the interaction of the PD-1 receptor ligand with the tumor and T cells to prevent suppression of the immune response. CheckMate 141 evaluated the efficacy, safety, and quality of life of nivolumab monotherapy versus standard single agent of the investigator’s choice (IC) in patients with recurrent/metastatic HNSCC. Nivolumab demonstrates significant overall survival and a favorable safety profile after long term follow-up [161]. Nivolumab was approved by the FDA and the National Institute of Health and Care Excellence (NICE) and Scottish Medicines Consortium (SMC) in the UK to treat progressive recurrent or metastatic SCC of the head and neck, or after platinum-based therapy.

Durvalumab works through the PD-1 receptor/ligand pathway. It inhibits the binding of PD-L1. A randomized, multicenter, global, phase 2 trial (CONDOR) of durvalumab monotherapy versus durvalumab in combination with tremelimumab (anti-CTLA-4), in patients with recurrent or metastatic SCC of the head and neck and low PD-L1 expression showed similar efficacy and durvalumab as a monotherapy showed an acceptable toxicity profile [162].

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